Antithrombotic therapy is a cornerstone of acute ischemic stroke (AIS) management and secondary stroke prevention. Since the first version of the Korean Clinical Practice Guideline (CPG) for stroke was issued in 2009, significant progress has been made in antithrombotic therapy for patients with AIS, including dual antiplatelet therapy in acute minor ischemic stroke or high-risk transient ischemic stroke and early oral anticoagulation in AIS with atrial fibrillation. The evidence is widely accepted by stroke experts and has changed clinical practice. Accordingly, the CPG Committee of the Korean Stroke Society (KSS) decided to update the Korean Stroke CPG for antithrombotic therapy for AIS. The writing members of the CPG committee of the KSS reviewed recent evidence, including clinical trials and relevant literature, and revised recommendations. A total of 35 experts were invited from the KSS to reach a consensus on the revised recommendations. The current guideline update aims to assist healthcare providers in making well-informed decisions and improving the quality of acute stroke care. However, the ultimate treatment decision should be made using a holistic approach, considering the specific medical conditions of individual patients.
Previously, aspirin was the only antithrombotic therapy with a proven efficacy for preventing early recurrent stroke and death or dependency in patients with acute ischemic stroke (AIS) in large clinical trials [
Long-term oral anticoagulation with non-vitamin K antagonist (NOAC) or warfarin is strongly recommended for secondary stroke prevention in patients with atrial fibrillation (AF) and ischemic stroke or TIA [
To reflect the accumulated evidence, the CPG Committee of the KSS decided to revise the Korean CPG for stroke to provide up-to-date recommendations for antithrombotic therapy in patients with AIS or TIA. The purpose of the current guideline update is to help make well-informed decisions and improve the quality of care for antithrombotic management. The ultimate treatment decision must be made by responsible healthcare providers, patients, and/or their caregivers.
The previous 2009 Korean CPG for antiplatelet therapy and the 2014 Korean CPG for anticoagulant therapy provided the following recommendations for patients with AIS or TIA [
1. In the hemorrhage-excluded, AIS patients, the oral administration of aspirin should start within 24 to 48 hours of onset (the loading dose 160 to 300 mg) (level of evidence [LOE]: Ia, grade of recommendation [GOR]: A).
2. Aspirin cannot replace acute interventions including intravenous thrombolysis (LOE: Ia, GOR: A).
3. Aspirin should not be taken within 24 hours of thrombolysis (LOE: Ia, GOR: A).
4. Intravenous injection of the glycoprotein IIb/IIIa receptor antagonists, including abciximab, is not recommended in patients with AIS (LOE: Ib, GOR: A).
1. There is no scientific evidence of the usefulness of heparin used within 48 hours of ischemic cerebral infarction. It might increase the risk of bleeding, compared with aspirin (LOE: Ia, GOR: A).
2. Low molecular weight heparin or heparinoids is not recommended as an early treatment of cerebral infarction (LOE: Ia, GOR: A).
3. Use of anticoagulants within 24 hours of recombinant tissue plasminogen activator administration is not recommended (LOE: IIa, GOR: B).
In May 2019, the Guideline Oversight Committee of the KSS decided to update the Korean CPG for antithrombotic therapy in patients with AIS or TIA and appointed members of the writing group recommended by the CPG Committee of the KSS. To achieve consensus, the CPG Committee organized an expert panel consisting of 35 experts. The writing group prepared revised recommendations, and expert panel members reached a consensus after two Delphi rounds in May 2020. The Guideline Oversight Committee reviewed and approved drafts prepared by the writing group.
For the updated information on antithrombotic therapy in AIS or TIA, we searched and assessed the results of randomized controlled trials (RCTs), pooled analyses, and updated major international guidelines published between January 2009 and May 2020. Additionally, we reviewed relevant articles solicited by experts who participated in the current guideline update.
For each recommendation, the LOE and GOR were determined based on the US Agency for Healthcare Policy and Research (currently the Agency for Healthcare Research and Quality) criteria (
The CHANCE trial randomized 5,170 Chinese patients with acute minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤3) or high-risk TIA (ABCD2 score ≥4) within 24 hours of symptom onset to combination therapy with clopidogrel (300 mg loading on day 1 followed by 75 mg once daily for 90 days) and aspirin (75 to 300 mg on day 1 followed by 75 mg once daily for the first 21 days) or aspirin monotherapy (75 to 300 mg on day 1 followed by 75 mg once daily for 90 days) [
Compared with the aspirin monotherapy group, the clopidogrel plus aspirin group had a significantly lower risk of the primary efficacy outcome of any recurrent stroke (ischemic or hemorrhagic) at 90 days (8.2% vs. 11.7%; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.57 to 0.81;
The POINT trial was designed earlier, but was completed later than the CHANCE trial. Similar to the CHANCE trial, the POINT trial enrolled 4,881 patients with acute minor ischemic stroke (NIHSS score ≤3) or high-risk TIA (ABCD2 score ≥4) from 10 countries in North America, Europe, Australia, and New Zealand. In contrast to the CHANCE trial, the POINT trial randomized patients within 12 hours after symptom onset, used a 600-mg loading dose of clopidogrel and 90 days of clopidogrel plus aspirin in the DAPT group, and enrolled patients with diverse ethnicities (predominantly white) [
Compared to the aspirin monotherapy group, the DAPT group had a significantly lower risk of the primary efficacy outcome at 90 days (5.0% vs. 6.5%; HR, 0.75; 95% CI, 0.59 to 0.95;
In
In a pooled individual patient-level data analysis of the CHANCE and POINT trials (n=10,051), compared with aspirin monotherapy, clopidogrel plus aspirin significantly reduced the risk of major ischemic events (ischemic stroke, myocardial infarction, or ischemic vascular death) (6.5% vs. 9.1%; HR, 0.70; 95% CI, 0.61 to 0.81;
In the time-course analysis, the benefit of DAPT for major ischemic events was largely achieved within the first 21 days (5.2% vs. 7.8%; HR, 0.66; 95% CI, 0.56 to 0.77;
The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial compared triple antiplatelet therapy (aspirin, dipyridamole, and clopidogrel) and standard therapy (clopidogrel monotherapy or aspirin plus dipyridamole) in patients with acute non-cardioembolic ischemic stroke (presenting with limb weakness, dysphasia, or neuroimaging-positive hemianopia) or TIA (presenting with at least 10 minutes of limb weakness or isolated dysphasia) within 48 hours from symptom onset [
There was no difference in the primary efficacy outcome (incidence and severity of recurrent stroke or TIA at 90 days) between the triple and standard therapy groups (6% vs. 7%; adjusted common odds ratio [OR], 0.90; 95% CI, 0.67 to 1.20;
The Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial compared ticagrelor and aspirin in patients with acute minor ischemic stroke (NIHSS score ≤5) or high-risk TIA (ABCD2 score ≥4) within 24 hours of symptom onset [
Compared to aspirin, ticagrelor did not significantly reduce the primary endpoint of the composite of recurrent stroke, myocardial infarction, or death at 90 days (6.7% vs. 7.5%; HR, 0.89; 95% CI, 0.78 to 1.01;
The Acute Stroke or Transient Ischaemic Attack Treated with Ticagrelor and Acetylsalicylic acid for Prevention of Stroke and Death (THALES) trial was published after completing our consensus achievement for this guideline update; therefore, we have not reflected the results of the THALES trial in the updated recommendations. In brief, the THALES trial compared ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on day 1 followed by 75 to 100 mg daily) versus aspirin monotherapy in 11,016 patients with acute minor ischemic stroke (NIHSS score ≤5) or high-risk TIA (ABCD2 score ≥6 or relevant intracranial or extracranial stenosis ≥50%) within 24 hours of symptom onset [
The previous recommendation to avoid antithrombotic therapy within the first 24 hours after intravenous thrombolysis (IVT) was based on expert consensus. No RCT has investigated the timing of antithrombotic initiation after IVT, and data from well-designed observational studies are scarce. A single-center observational study in Korea reported that the early administration of antithrombotics within 24 hours after reperfusion therapy was safe. In this study, of 712 patients treated with reperfusion therapy (34% IVT only, 34% IVT plus mechanical thrombectomy [MT], and 32% MT only), 456 (64%) patients received antithrombotic therapy within 24 hours after reperfusion therapy. Early initiation of antithrombotic therapy within 24 hours as compared to late initiation after 24 hours did not increase the risk of symptomatic HT (3.3% vs. 3.1%; adjusted OR, 0.85; 95% CI, 0.35 to 2.10). Any HT was even lower in the early initiation group (adjusted OR, 0.56; 95% CI, 0.35 to 0.89). The rate of 3-month favorable outcomes (modified Rankin Scale [mRS] score 0–1) was comparable between the early and late initiation groups (39.3% vs. 34.8%; OR, 1.09; 95% CI, 0.75 to 1.59). In the interaction analysis, the modality of reperfusion therapy (IVT, IVT plus MT, or MT) did not modify the associations between the initiation timing and symptomatic HT, any HT, or mRS outcome [
The Cilostazol in Acute Ischemic Stroke Treatment (CAIST) trial conducted in Korea was a randomized double-blind non-inferiority trial that compared cilostazol 200 mg/day and aspirin 300 mg/day in 458 patients with AIS (NIHSS ≤15) within 48 hours of symptom onset for 90 days [
An earlier RCT failed to demonstrate the safety and efficacy of IV abciximab in patients with AIS [
Two recent Korean observational studies reported the safety and feasibility of IV or intra-arterial tirofiban in patients with acute atherosclerotic large artery occlusion who underwent MT. In one study of 118 patients with residual stenosis after MT, the tirofiban group (n=59) had a higher final successful recanalization rate (81.4% vs. 42.4%, P=0.016) and a numerically lower rate of major intracranial bleeding of parenchymal hematoma type 2 and/or thick subarachnoid hemorrhages (15.3% vs. 5.1%,
Long-term oral anticoagulation therapy with NOAC or warfarin is strongly recommended for secondary stroke prevention in patients with AF with prior ischemic stroke or TIA [
Parenteral anticoagulation is not recommended because the benefit is offset by an increased risk of ICH [
The Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation (RAF) study evaluated the risk of recurrent ischemic events and severe bleeding with anticoagulation regimens and the optimal timing for initiating anticoagulation. A total of 1,029 patients with AF with AIS were enrolled from 29 centers in European and Asian countries [
The Clinical Relevance Of Microbleeds In Stroke-2 (CROMIS-2) study, a multicenter observation study from the United Kingdom and Netherlands, compared the 90-day clinical outcomes between 358 patients with early oral anticoagulation initiation (0 to 4 days after AIS or TIA) and 997 with late oral anticoagulation (≥5 days or never started) [
Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-Non-Valvular Atrial Fibrillation (SAMURAI-NVAF), a Japanese multicenter observational study, compared the risks of stroke or SE and major bleeding between 475 patients who were treated with NOACs and 662 treated with warfarin during hospitalization for AIS. The median interval from stroke onset to initiating oral anticoagulant therapy was 3 days (IQR, 1 to 8) in the warfarin group and 4 days (IQR, 2 to 7) in the NOAC group; the median NIHSS scores at admission were 11 (IQR, 4 to 20) and 4 (IQR, 1 to 13), respectively. During 90 days, the NOAC group compared with the warfarin group had a similar risk of stroke or SE (2.84% vs. 3.09%; adjusted HR, 0.96; 95% CI, 0.44 to 2.04) and a nonsignificant reduction in the occurrence of major bleeding (1.11% vs. 2.61%; adjusted HR, 0.63; 95% CI, 0.19 to 1.78) [
The subsequent SAMURAI-NVAF study compared outcomes between 223 patients with early NOAC initiation (0 to 3 days after AIS or TIA, median 2 day [IQR, 1 to 3]) and 276 with late NOAC initiation (≥4 days, median 6 days [IQR, 5 to 9]) [
Observational studies have reported the potential role of early NOAC use in patients with AF and AIS or TIA. However, these studies had limitations of indication bias and included mild stroke severity in the majority of patients.
The Acute Stroke With Xarelto to Reduce Intracranial Hemorrhage, Recurrent Embolic Stroke, and Hospital Stay (Triple AXEL) was a randomized, multicenter, open-label, phase 2 trial that was conducted in Korea between April 2014 and December 2015 [
The rivaroxaban and warfarin groups did not differ in the primary end point, a composite of new ischemic lesion or new ICH seen on follow-up magnetic resonance imaging at 4 weeks (49.5% vs. 54.5%; relative risk [RR], 0.91; 95% CI, 0.69 to 1.12;
Currently, four RCTs are underway to compare early versus late initiation of NOAC in patients with AF-related AIS, which will enroll a total of 9,974 patients: 2,000 in the Early Versus Late Initiation of Direct Oral Anticoagulants in Post-ischaemic Stroke Patients with Atrial fibrillation (ELAN) trial, 3,474 in the OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke (OPTIMAS) trial, 3,000 in the Timing of oral anticoagulant therapy in acute ischemic stroke with atrial fibrillation (TIMING) trial, and 1,500 in the Optimal Delay Time to Initiate Anticoagulation After Ischemic Stroke in Atrial Fibrillation (START) trial. The results of these trials will guide healthcare providers to establish the optimal timing for early NOAC use in patients with AF and AIS.
We convened a panel of 35 expert neurologists from the KSS to reach a consensus with the modified Delphi method. The expert panel members were asked to provide their ratings for each recommendation on a 9-point scale (a score of 9 represented strong agreement and a score of 1 represented strong disagreement) modified from the Research AND Development Corporation method [
All 35 panel members provided their ratings (list of experts is in
Updated recommendations for the use of antithrombotic agents in patients with AIS are summarized in
The current guideline update focused on antiplatelet therapy in minor AIS or high-risk TIA presenting within 24 hours from onset and early oral anticoagulation in AIS with AF. According to the current Clinical Research Collaboration for Stroke in Korea Statistics 2020 Report in Korea, 29.7% of all patients with ischemic stroke arrived at a hospital within 24 hours of onset and had mild severity (NIHSS score ≤3), and 7.4% had AF and relatively mild stroke severity [
Supplementary materials related to this article can be found online at
Results of Delphi Consensus
Comparison of changes in recommendations between previous and revised guidelines
The authors have no financial conflicts of interest.
Level of evidence and grade of recommendation
Level of evidence (LOE) | ||
Ia | Evidence obtained from meta-analysis of randomized controlled trials | |
Ib | Evidence obtained from at least one randomized controlled trial | |
IIa | Evidence obtained from at least one well-designed controlled study without randomization | |
IIb | Evidence obtained from at least one other type of well-designed quasi-experimental study | |
III | Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies | |
IV | Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities | |
Grade of recommendation (GOR) | ||
A (LOE Ia, Ib) | Required: at least one randomized controlled trial as part of the body of literature of overall good quality and consistency addressing specific recommendation | |
B (LOE IIa, IIb, III) | Required: availability of well conducted clinical studies but no randomized clinical trials on the topic of recommendation | |
C (LOE IV) | Required: evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. This grade indicates the absence of directly applicable clinical studies of good quality. | |
GPP (good practice points) | Recommended best practice based on the clinical experience of the guideline development group |
Summary of current recommendation
Comment | ||
---|---|---|
Antiplatelet agents | ||
1. In the hemorrhage-excluded, acute ischemic stroke patients, the oral administration of aspirin should start within 24 to 48 hours of onset (the loading dose 160–300 mg) (LOE: Ia, GOR: A). | No change | |
2. Aspirin cannot replace acute interventions including intravenous tPA (LOE: Ia, GOR: A). | No change | |
3. For patients treated with intravenous thrombolysis, it is generally recommended to delay antithrombotic therapy up to 24 hours. However, when the benefit is expected to outweigh the risk, antithrombotic therapy may be initiated within 24 hours after intravenous tPA (LOE: III, GOR: B). | Revised from the previous recommendation | |
4. In general, intravenous glycoprotein IIb/IIIa receptor antagonists is not recommended in patients with acute ischemic stroke (LOE: Ib, GOR: A). However, intravenous and/or intra-arterial use of glycoprotein IIb/IIIa receptor antagonists can be considered in highly selected patients who require rescue therapy during mechanical thrombectomy or emergent angioplasty/stenting, taking into account benefit and risk (LOE: IV, GOR: C). | Revised from the previous recommendation | |
5. In patients presenting with acute minor ischemic stroke (NIHSS score 0–3) or high-risk TIA (ABCD2 score ≥4), dual antiplatelet therapy with aspirin and clopidogrel initiated within 24 hours from the onset and maintained for up to 21–30 days is recommended to further reduce the risk of early recurrent stroke and major ischemic event (LOE: Ia, GOR: A). | New recommendation | |
Anticoagulants | ||
1. There is no scientific evidence on the usefulness of heparin used within 48 hours of ischemic cerebral infarction. It might increase the risk of bleeding, compared with aspirin (LOE: Ia, GOR: A). | No change | |
2. LMWH or heparinoids is not recommended as an early treatment of cerebral infarction (LOE: Ia, GOR: A). | No change | |
3. Use of anticoagulants within 24 hours of intravenous tPA administration is not recommended (LOE: IIa, GOR: B). | No change | |
4. For patients with acute ischemic stroke and atrial fibrillation, it is recommended to start oral anticoagulation when the risk of hemorrhagic transformation is expected to be low. It may be reasonable to start oral anticoagulation between 4 and 14 days after stroke onset. However, in patients with a high risk of recurrent stroke and low risk of hemorrhagic transformation, oral anticoagulation might be initiated within 5 days from stroke onset (LOE: III, GOR: B). | New recommendation |
LOE, level of evidence; GOR, grade of recommendations; tPA, tissue plasminogen activator; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack; LMWH, low molecular weight heparin.